Between August 5 and 27, 2009, Ms. Diane Van Leeuwen, representing the Food and Drug Administration (FDA), conducted an investigation and met with you to review your conduct of the following clinical investigations:

• Protocol (b)(4), entitled “(b)(4)” of the investigational drug (b)(4), performed for (b)(4).; and

• Protocol (b)(4), entitled “(b)(4),” of the investigational drug (b)(4), performed for (b)(4).

This inspection is a part of the FDA's Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects of those studies have been protected.

From our review of the establishment inspection report, the documents submitted with that report, and your September 14, 2009 written response, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. We are aware that at the conclusion of the inspection, Ms. Van Leeuwen presented and discussed with you Form FDA 483, Inspectional Observations. We wish to emphasize the following:

Regarding Protocol (b)(4):

1. You failed to conduct the studies or ensure they were conducted according to the investigational plans [21 CFR 312.60].

a. Protocol (b)(4), Section 7.4.1 (Dose Escalation and Modification) specified study drug dosages to be administered based on assigned cohort. Subject 008 was assigned to Cohort 4, with a study drug dose specification of 150 mg/m2. For Cycle 4, Day 1 on September 3, 2008, the subject's height and weight were recorded as 5’0” and 132 lbs., respectively. The subject's body surface area was documented as 1.59 m2, and the dose was inaccurately calculated and recorded as 274.5 mg. The correct dosage should have been calculated as 238.5 mg [150 mg/m2 x 1.59 m2]. The subject's chemotherapy flow sheet documents that the subject received 274.5 mg of study drug on September 3, 2008. The administration of this miscalculated dose unnecessarily exposed the subject to an overdose, with the potential for increased adverse events.

In your September 14, 2009, written response, you indicated that the subject's chart was reviewed with the study nurses and pharmacists, and the dosing error was confirmed. As corrective measures, you indicated that your site's nurses and pharmacists were retrained on study dosing requirements and chart documentation of calculation parameters (height/weight), with a reminder to ensure consistency of data and dosing changes. Additionally, you noted that your site has implemented a policy whereby a nurse or pharmacist double-checks dosages prior to all study-related infusions. We acknowledge your response and find your corrective measures to prevent future recurrence acceptable.

b. Protocol (b)(4) Section 10.1.1 (Pharmacokinetics) required samples to be drawn on Day 1 at pre-dose, and at 15 minutes, 30 minutes, 45 minutes, 1 hour, and 2 hours after study drug infusion was initiated. The following subjects’ pharmacokinetic (PK) samples were drawn at the incorrect time intervals. Specifically, the samples were collected after the completion of the infusion rather than after the initiation of the infusion:

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 002 Day 1 Study Drug Infusion Time: 1330-1405

Subject 002 Day 1 Study Drug Infusion Time: 1330-1405

Subject 002 Day 1 Study Drug Infusion Time: 1330-1405

Just prior to dose

Just prior to dose

1325

15 minutes (post infusion initiation)

1345

1420

30 minutes (post infusion initiation)

1400

1435

45 minutes (post infusion initiation)

1415

1450

1 hour (post infusion initiation)

1430

1505

2 hours (post infusion initiation)

1530

1605

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 003 Day 1 Study Drug Infusion Time: 1420-1452

Subject 003 Day 1 Study Drug Infusion Time: 1420-1452

Subject 003 Day 1 Study Drug Infusion Time: 1420-1452

Just prior to dose

Just prior to dose

1330

15 minutes (post infusion initiation)

1435

1510

30 minutes (post infusion initiation)

1450

1525

45 minutes (post infusion initiation)

1505

1540

1 hour (post infusion initiation)

1520

1555

2 hours (post infusion initiation)

1620

1655

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 004 Day 1 Study Drug Infusion Time: 1440-1514

Subject 004 Day 1 Study Drug Infusion Time: 1440-1514

Subject 004 Day 1 Study Drug Infusion Time: 1440-1514

Just prior to dose

Just prior to dose

1330

15 minutes (post infusion initiation)

1455

1530

30 minutes (post infusion initiation)

1510

1545

45 minutes (post infusion initiation)

1525

1600

1 hour (post infusion initiation)

1540

1615

2 hours (post infusion initiation)

1640

1716

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 005 Day 1 Study Drug Infusion Time: 1245-1316

Subject 005 Day 1 Study Drug Infusion Time: 1245-1316

Subject 005 Day 1 Study Drug Infusion Time: 1245-1316

Just prior to dose

Just prior to dose

1220

15 minutes (post infusion initiation)

1300

1335

30 minutes (post infusion initiation)

1315

1347

45 minutes (post infusion initiation)

1330

1403

1 hour (post infusion initiation)

1345

1418

2 hours (post infusion initiation)

1445

1518

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 006 Day 1 Study Drug Infusion Time: 1222-1254

Subject 006 Day 1 Study Drug Infusion Time: 1222-1254

Subject 006 Day 1 Study Drug Infusion Time: 1222-1254

Just prior to dose

Just prior to dose

1140

15 minutes (post infusion initiation)

1237

1310

30 minutes (post infusion initiation)

1252

1325

45 minutes (post infusion initiation)

1307

1340

1 hour (post infusion initiation)

1322

1355

2 hours (post infusion initiation)

1422

1455

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 010 Day 1 Study Drug Infusion Time: 1330-1402

Subject 010 Day 1 Study Drug Infusion Time: 1330-1402

Subject 010 Day 1 Study Drug Infusion Time: 1330-1402

Just prior to dose

Just prior to dose

1315

15 minutes (post infusion initiation)

1345

1417

30 minutes (post infusion initiation)

1400

1432

45 minutes (post infusion initiation)

1415

1447

1 hour (post infusion initiation)

1430

1502

2 hours (post infusion initiation)

1530

1602

Protocol-specified PK sampling schedule (post infusion initiation)

PK sampling time according to protocol (2400 hours)

Actual time of PK sampling (2400 hours)

Subject 012 Day 1 Study Drug Infusion Time: 1521-1555

Subject 012 Day 1 Study Drug Infusion Time: 1521-1555

Subject 012 Day 1 Study Drug Infusion Time: 1521-1555

Just prior to dose

Just prior to dose

1420

15 minutes (post infusion initiation)

1536

1611

30 minutes (post infusion initiation)

1551

1632

45 minutes (post infusion initiation)

1606

1648

1 hour (post infusion initiation)

1621

1700

2 hours (post infusion initiation)

1721

1758

In your September 14, 2009, written response, you indicated that your site misunderstood the timing of the PK samples. You noted that your site interpreted the protocol-required PK sampling to begin at the end of the drug infusion time rather than at the start of the drug infusion time. You stated that your site will pay particular attention to the protocol requirement for PK sampling in the future. We acknowledge your response. However, we are concerned that the response is not adequate to prevent future recurrence of the violation noted above. In particular, we are concerned that you did not properly understand the protocol specified PK sampling schedule from the start of the study, and that you did not ensure that the PK samples were collected according to the protocol throughout the study. Your failure to collect PK samples as specified in the protocol significantly undermines the reliability and integrity of the data captured at your site.

Regarding Protocols (b)(4) and (b)(4)

2. You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation [21 CFR 312.62(b)].

The inspection revealed that there were numerous adverse events recorded in progress notes of subjects' records that had not been reported on the case report forms (CRFs), and there was no explanation regarding this discrepancy. The following are examples of adverse events that had not been reported on the electronic CRFs at the time of the inspection. Note that since the inspection occurred in August 2009, the examples below represent delays in transcribing adverse events from progress notes to electronic CRFs that range from at least 8 months to 15 months.

In your September 14, 2009 written response, you stated that your site staff enters all adverse events and concomitant medications in subjects' charts at the time of each visit. You indicated that at the start of the study, your site staff members were entering data (adverse events and concomitant medications) in CRFs prior to the sponsor's monitoring visits. However, you indicated that your site staff stopped entering data in CRFs in advance of the monitoring visits so that they could enter data with the monitors present, to avoid additional system queries. As a corrective measure, you noted that your site staff members have implemented a policy requiring that all CRFs be completed in a timely manner, defined as 30 days following a study visit, regardless of scheduled monitoring visits.

We acknowledge your response. However, the lack of timely adverse event information in the electronic CRFs may have jeopardized subject safety as well as the reliability and integrity of the data captured on the CRFs at your site. We find your corrective measures to prevent future recurrence to be acceptable, if implemented as proposed.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address these deficiencies and establish procedures to ensure that any ongoing or future studies will be in compliance with FDA regulations.

Within fifteen (15) working days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to adequately and promptly explain the violations noted above may result in regulatory action without further notice.

If you have any questions, please contact Constance Cullity (formerly Lewin), M.D., M.P.H., at 301-796-3397; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to:

Sincerely yours,{See appended electronic signature page}Leslie K. Ball, M.D.DirectorDivision of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchFood and Drug Administration----------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.----------------------------------------------------------------------------------------/s/----------------------------------------------------LESLIE K BALL03/17/2010